Integrated Genomic and Transcriptomic Analysis Improves Disease Classification and Risk Stratification of MDS with Ring Sideroblasts

PURPOSE: Ring sideroblasts (RS) define the low-risk myelodysplastic neoplasm (MDS) subgroup with RS but may also reflect erythroid dysplasia in higher risk myeloid neoplasm. The benign behavior of MDS with RS (MDS(RS+)) is limited to SF3B1-mutated cases without additional high-risk genetic events, but one third of MDS(RS+) carry no SF3B1 mutation, suggesting that different molecular mechanisms may underlie RS formation. We integrated genomic and transcriptomic analyses to evaluate whether transcriptome profiles may improve current risk stratification. EXPERIMENTAL DESIGN: We studied a prospective cohort of MDS(RS+) patients irrespective of World Health Organization (WHO) class with regard to somatic mutations, copy-number alterations, and bone marrow CD34(+) cell transcriptomes to assess whether transcriptome profiles add to prognostication and provide input on disease classification. RESULTS: SF3B1, SRSF2, or TP53 multihit mutations were found in 89% of MDS(RS+) cases, and each mutation category was associated with distinct clinical outcome, gene expression, and alternative splicing profiles. Unsupervised clustering analysis identified three clusters with distinct hemopoietic stem and progenitor (HSPC) composition, which only partially overlapped with mutation groups. IPSS-M and the transcriptome-defined proportion of megakaryocyte/erythroid progenitors (MEP) independently predicted survival in multivariable analysis. CONCLUSIONS: These results provide essential input on the molecular basis of SF3B1-unmutated MDS(RS+) and propose HSPC quantification as a prognostic marker in myeloid neoplasms with RS.